Antiviral agents vaccines and immunotherapies - part 2 ppt

Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 31 Indinavir IDV Erythematous macules and papules, dry skin, alopecia, paronychia, pyogenic granulomas and others listed under SQV; rare: Stevens-Johnson syndrome Nephrolithiasis, renal insufficiency or renal failure; pharyngitis, gastrointestinal upset, anemia, hepatitis and other listed under SQV and RTV Same as listed under SQV and RTV Nelfinavir NFV Same as listed under SQV Diarrhea and other as listed under SQV and RTV Same as listed under SQV and RTV Amprenavir APV Macules and papules +/ − pruritis; Rare: Stevens-Johnson syndrome; others as listed under SQV Perioral paraesthesias, diarrhea, headache, nausea/vomiting and others listed under SQV and RTV As listed under SQV and RTV Lopinavir As listed under SQV Diarrhea and others listed under SQV and RTV As listed under SQV and RTV Fosamprenavir GW 433908 “Rash” 1% develop Stevens- Johnson syndrome Nausea, diarrhea Sulfonamide, lovastatin, simavastatin, triazolam, midazolam, ergot-based drugs, cisapride, pimozole Atazanavir BMS–232632 Diarrhea, jaundice Enfuviritide ENF, T-20 Injection site reactions Allergic reactions, pain or numbness in feet or legs, decreased appetite, weakness, constipation, pancreatitits 32 Antiviral Agents avenues for therapy. These include inhibitors that are active during the binding, fusion, and entry of the viral capsid into the cell. Then, during RNA replication, reverse transcriptase drugs interfere with RNA replication. Viral integrase drugs (of which there are none approved at this writing) interfere with entry into the nucleus. Another potential, but not yet having any approved drugs, target would be the viral zinc- finger nucleocapsid proteins. Finally, viral protease inhibitors attack the virus as it leaves the cell to infect other cells. (See Fig. 2.2) Fig. 2.2 Sites of action of antiretroviral drugs. Nucleoside, nucleotide and non-nucleoside reverse transcriptase (RT) inhibitors act at the same step in the replication of HIV. Nucleoside analogues, when phosphorylated, competitively inhibit RT by acting as an alternative substrate for the enzyme. Non-nucleoside analogues do not require phosphorylation but noncompetitively bind directly to the active site of RT. Protease inhibitors prevent the cleavage of viral polyproteins in the final stage of viral protein processing, thus preventing the assembly of mature HIV virions. Fusion inhibitors prevent binding to the surface of the cell and subsequent infection of the cell. Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 33 Treatments for HIV. There is no known “cure” for HIV disease. The initial regimen programs for HIV began with nucleoside reverse transcriptase inhibitors (NRTIs) in 1987 and therapy was with one drug, zidovudine Over time, it became obvious that as HIV replicated, it also mutated. This meant that therapy began to fail. Progress (rising CD4 + counts and lowered HIV RNA levels) began to unravel. Other drugs, administered individually, were no better. However, combinations of antiretroviral drugs provided a “cocktail” that attacked the virus at multiple points (12). This HAART became the standard of care in 1996 in developed countries where insurance or government health care pays for the nearly $20,000 bill for drugs prescribed for a patient each year. In developing countries, however, monotherapy may be the only option, if any antiretroviral therapy is available. Figures 2.1 and 2.2 illustrate the available therapies that can be used in HAART and their sites of action. Typically HAART consists of two nucleoside analogues and a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Today there is an armada of antiretrovirals in the arsenal with many more being developed (Fig. 2.2). Nucleotide and nucleoside reverse transcriptase inhibitors, PIs, and NNRTIs have been joined by fusion inhibitors. Selecting the appropriate therapy, however, is no longer a simple matter. There have been several suggested therapy cocktails con- sisting of three or even four antiretrovirals taken concur- rently. The “original combination therapy” called for two NRTIs administered with one NNRTI or a PI. (13,14) Recent studies indicate that a combination of three anti- virals appears most efficacious and that efavirenz, lamivudine, and zidovudine provide the best combination for patients receiving their first HIV medication. At this time, lamivudine and zidovudine are available as a combination pill (Com- bivir ® ). This combination drug, administered with efavirenz, means patients take only three pills/day with a concomitant increase in patient compliance. If resistance is detected, the patient and doctor must con- sider other antiretroviral drugs as alternative therapy. The 34 Antiviral Agents options may appear numerous, but many factors enter into the picture. Once resistance occurs, other related drugs may demonstrate cross-resistance. Allergies to one drug usually transfer to other drugs in the same category. Concomitant non-antiretroviral drugs also must be considered. For exam- ple, prescribing a drug known to cause hepatic toxicity might prove to be risky to a patient with any type of hepatitis. Like- wise, any drug that affects liver metabolism must be used with extreme care if given along with other agents metabo- lized by the liver. Controversy still exists regarding the optimal time to initiate therapy due to the cost of treatment, the side effects, and the difficulty with compliance which results in potential resistance. Newly revised guidelines on treating adults and adolescents with HIV and AIDS provide suggestions for regimens that are more definitive. The guidelines were prepared by the Panel on Clinical Practices for Treatment of HIV Infec- tion, convened by the Department of Health and Human Ser- vices. For the first time, the guidelines include lists of “preferred” and “alternative” regimens. These lists are available at http://aidsinfo.nih.gov; the document also lists regimens or components that should never be offered. The preferred regimen based on NNRTIs calls for a combination of efavirenz, lamivudine, and zidovudine, tenofovir or stavudine, except for women who are pregnant or may become pregnant. Patients on this regimen take three to five pills per day. The preferred regimen based on PIs calls for a combina- tioin of lopinavir/ritonavir (coformulated as Kaletra ® ) together with lamivudine and either zidovudine or stavudine. Patients on this regimen take 8 to 10 pills per day. Triple NRTI regimens should be used only when an NNRTI- or PI-based regimen cannot be used as first-line therapy. The panel’s preferred triple-NRTI regimen calls for a combination of abacavir, lamivudine, and either zidovudine or stavudine. Patients on this regimen take two to six pills per day. Regimens listed as “alternative” in the guidelines, however, may actually be the preferred regimen for a specific patient. Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 35 The panel listed 12 regimens or components that should never be offered. Several, including monotherapy and dual nucleoside therapy, had been listed as contraindicated in previ- ous versions of the guidelines. The newly listed contraindicated regimens are a three-NRTI regimen with abacavir, tenofovir, and lamivudine (because of early virologic nonresponse); a three-NRTI regimen with didanosine, tenofovir, and lamivudine (because of a high rate of virologic failure); the combination of didanosine and stavudine (because of a high incidence of tox- icities, including several deaths); the combination of atazanavir and indinavir (both of which can cause high-grade hyperbiliru- binemia and jaundice); and emtricitabine plus lamivudine as a two-NRTI backbone (since both drugs have similar resistance profiles and minimal additive antiviral activity). The guidelines found at www.hivatis.org recommend initiation of treatment for all HIV-infected persons who have symptoms of HIV infection, a rapidly declining CD4 count, a CD4 count <200–350 cells/mm 3 , or a viral load >30,000 RNA copies/ml (bDNA assay) or 55,000 RNA copies ml (RT-PCR assay) (regardless of the CD4 count) (15). Guidelines are less established for pediatric patients, but it is generally recommended that therapy be initiated in children with clinical symptoms of HIV infection or evidence of immunosuppression, regardless of viral load. However, any child with HIV RNA levels >100,000 copies/ml is at a high risk for mortality, and antiretroviral therapy should be started. Others recommended starting therapy in children at HIV RNA levels >10,000–20,000 copies/ml. Zidovudine (AZT) monotherapy is indicated only for infants of indeterminate HIV status during the first six weeks of life to prevent perinatal HIV transmission (16). Even combination therapy has many side effects that HIV-infected persons must tolerate. Side effects and the required number of pills to be taken daily affect patient compliance. Even missing 5% of one’s pills may put a patient at risk for drug resistance. These factors have led to the develop- ment of more potent and safer antiretroviral agents. Although resistance is less likely with HAART than with monotherapy, it remains a problem. 36 Antiviral Agents Combination therapies. To address the need for fewer pills, pharmaceutical companies have begun to market combination therapies. Three of these are currently marketed. Zidovudine and lamivudine are marketed as Combivir. A combination of abacavir, zidovudine, and lamivudine is marketed as Trizivir ® . Lopinavir, which was approved only as a combination drug with ritonavir, is marketed in this combination as Kaletra. Maintenance therapy after combination therapy. One study of maintenance therapy of HIV infection (after an initial response to combination therapy) showed that suppression of plasma HIV RNA was better sustained with a combination of indinavir, zidovudine, and lamivudine than either indinavir alone or zidovudine and lamvudine (17). A similar study also found that three-drug therapy (zidovudine, lamivudine, and indinavir) was more effective than two-drug maintenance therapy (zidovudine plus lamivudine or zidovudine plus indinavir) in sustaining a reduced viral load in HIV-1–infected patients after three months of induc- tion therapy (18). These studies and others have led to the current thera- peutic approach to HIV, which involves HAART. These treatment guidelines suggest early and aggressive drug therapy with three antiretroviral drugs from different classes of drugs. In previously untreated patients, this approach is expected to reduce the plasma HIV virus levels to levels below the limits of detection (19). However, studies have shown that even with effective HAART therapy and unde- tectable plasma HIV virus levels, virus is still present in lymph nodes, semen, or possibly elsewhere. Furtado et al. (20) showed that despite treatment with potent antiretroviral drugs and suppression of plasma HIV-1 RNA, HIV transcrip- tion was actively present in peripheral blood mononuclear cells. Zhang et al. (21) found that several HIV-1–infected men on HAART therapy continued to have virus present in seminal cells, which may still allow for sexual transmission of the virus. Moreover, combination antiretrovirals appear to suppress HIV-1 replication in some, but not all, patients (22). Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 37 Regardless of these dilemmas, the leading problem with HAART therapy is its cost and availability. With the extremely high expense of daily combination treatment (i.e., $15,000 to $20,000 per year), more than 95% of the 46 million HIV- infected people worldwide cannot afford it. Further progress in the battle against HIV will require a more economic and accessible means of treatment that can reach the population in the developing world. Prophylactic antiretroviral drugs. Another advance in the treatment of HIV is the potential to administer prophylactic antiretroviral drugs to exposed individuals in order to decrease the risk of acquiring infection. Although large-scale, placebo-controlled clinical trials are not logistically possible, one study has found that zidovudine prophylaxis reduced HIV seroconversion after percutaneous exposure (23,24). Current basic recommendations for postexposure prophylaxis (PEP) include a four-week regimen of zidovudine and lamivudine, begun as soon as possible after exposure (25). For occupational HIV exposure with additional risk for transmission (e.g., higher virus titers or larger blood exposure), indinavir or nelfinavir is added to the basic regimen. Zidovudine chemoprophylaxis is also effective in the reduction of perinatal transmission, in some studies decreasing the risk of vertical transmission from mother to child by 66 to nearly 70% (26,27). This regimen consists of daily oral zidovudine given during the last six weeks of pregnancy, followed by intravenous zidovudine during labor (28). Thereaf- ter, the newborn is given oral zidovudine for the first six weeks of life. Implementation of this regimen in the United States and Europe has dropped the rate of perinatal transmission to 6% or less (29). However, the high expense of treatment is cost-prohibitive for developing countries. Three recent studies have evaluated the efficacy of short-term zidovudine in decreasing the risk of HIV-1 perinatal transmission. The trial regimens generally consisted of oral zidovudine given during the last four weeks of pregnancy, some with additional doses during labor. Results revealed a 37 to 38% decrease in vertical transmission of HIV-1 in subjects who 38 Antiviral Agents breastfed (30,31). In a similar study without breastfeeding, the reduction in the rate of transmission was 50% (32). While a shorter course of zidovudine is considerably cheaper, ($50 for the shorter course vs. $800 for the longer course), the cost of therapy remains too high for most developing countries. Musoke et al. (33) found that a single dose of nevirapine administered to HIV-positive women during labor and another dose given to their infants during the first week of life may be a safe and well-tolerated treatment that is helpful in reduc- ing perinatal transmission of HIV. This treatment would be a low-cost and accessible alternative for poor and developing countries with high rates of HIV infection and limited funds for treatment. Guidelines for therapy. The National Institutes of Health has defined general principles for the therapy of HIV (34). Both plasma HIV RNA levels (viral load) and CD4+ T cell counts should be followed for monitoring of response to treatment. The combination of these values has been determined to be a more accurate assessment of prognosis (35). In addition, they are a useful tool in determining the efficacy of antiretroviral treatment while the patient is awaiting clinical response. CD4+ counts indicate the extent of immune system damage and the risk for opportunistic infections. Although HIV RNA levels are more predictive of the risk for disease progression, CD4+ counts are a more accurate measurement of the effect of antiretroviral therapy. HIV RNA levels should begin to decline within days of effective treatment and ideally should progressively fall to below the limits of detection within eight weeks, although complete suppression is seen in a maximum of only 60–80% of previously untreated patients. A more realistic eight-week target is a one-log reduction of the viral load. Rebound of viral load levels during consistent treatment may indicate resistant HIV variants and may likely require changes in the current antiretroviral regimen. It should be noted that if one of the drugs in the antiretroviral regimen must be stopped, they all should be stopped and that a single-drug substitu- tion can be made only if the patient’s viral load is completely suppressed. Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 39 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Nucleoside analogs were the first line of defense for the treatment of HIV infection in 1987 (36). Subsequent studies of var- ious combination therapies of indinavir, zidovudine, and lamivudine led to the beginnings of general combination therapy and the refinement of HAART combination therapy. These early studies suggested that a prompt and aggressive drug therapy with three or more antiviral drugs from two or three classes of drugs might be more effective. HAART can reduce the plasma HIV virus levels to levels below the existing limits of detection (17). Mechanisms of action. Nucleoside analogues are dideoxy- nucleoside analogues which are phosphorylated intracellu- larly into active triphosphate metabolites. The active form then competitively inhibits HIV reverse transcriptase by acting as an alternate substrate for the enzyme. This family of compounds lacks the 3′-hydroxyl group, which leads to chain termination once the active metabolite is incorporated into the developing DNA strand. Figure 2.2 depicts the site of action of the existing and new antiretroviral drugs. Zidovudine [AZT] (Retrovir ® ) Zidovudine is the most extensively studied drug of all the antiretrovirals. It is no longer used as monotherapy, except in parts of the world where other antiretroviral drugs are not available. It has been widely prescribed by practitioners after early studies revealed improved survival rates and delayed declines in CD4 counts in patients with HIV infection (36–38). As a result of monotherapy with zidovudine, resistant HIV strains have developed, which have limited the efficacy of this treatment. After six months of therapy with zidovudine alone, HIV isolates with reduced susceptibility can be recovered (39,40). The quantity and frequency of resistant strains progressively increases over time with monotherapy. As HIV-1 strains develop resistance to zidovudine therapy, those resistant strains have been proven to be transmittable to other persons (41–45). There are studies underway to develop a 40 Antiviral Agents quantitative method to validate zidovudine resistance (46). There is a report that Korean red ginseng delays the develop- ment of resistance to zidovudine (47). The nucleoside analogue drugs are closely related and have similar mechanisms of action; there is cross-resistance among these compounds, but they have different side effect profiles (48). The structure of zidovudine, its brand names, and its approved usage are shown in Fig. 2.3. Zidovudine monotherapy is used for infants of indeterminate HIV status during the first six weeks of life to prevent HIV transmission (16). Adverse Events Phosphorylation of zidovudine. Poor phosphorylation of zidovudine has been implicated in the intracel- lular accumulation of zidovudine monophosphate. This accumulation is associated with cytotoxicity as mediat- ed through mitochondrial damage (49). Bone marrow suppression. The most frequently seen adverse effect of zidovudine is bone marrow suppression, with severe anemia and/or neutropenia. Coadministration with other drugs. Coadministra- tion with other drugs which may potentially suppress the bone marrow should be done cautiously, with fre- quent monitoring of hematologic parameters. Gastrointestinal upset and/or nausea. Fig. 2.3 Trade names, structure, and uses of Zidovudine. [...]... acid-bindingprotein type I, may bind to lipoprotein receptor-related proteins and result in hypertriglyceridemia and lipodystrophy (22 2) Abnormal adipose distribution Human aspartic proteases playing a role in adipose regulation may be downregulated by PIs, resulting in abnormal adipose deposition (22 3) Insulin resistance and associated cardiovascular risk Metformin reduces insulin resistance and related... reverse transcriptase ( 122 ) (See Fig 2. 2 for the site of action.) These drugs are not substrates for the reverse transcriptase enzyme and are not incorporated into the developing viral DNA chain They are also active in their native state and do not require phosphorylation to become an active metabolite ( 123 ) The NNRTIs are highly active for HIV-1, but have no activity against HIV -2 Resistance is a significant... ( 124 ) and cross-resistance occurs among members of this class ( 125 ) However, there is no cross-resistance with nucleoside analogues ( 126 ) The NNRTIs are a suitable addition for combination therapy, as they have in vitro synergistic activity with nucleoside analogues and PIs Nevirapine [NVP] (Viramune®) In 1996, nevirapine was the first NNRTI to become available The structure, brand names, and FDA-approved... appears to be more prevalent in women (131) and can be associated with eosinophilia and systemic symptoms (1 32) The rash becomes severe in 6 to 20 % of patients, some of whom develop Stevens-Johnson 56 Antiviral Agents syndrome (133) Short-term prednisone administration does not prevent nevirapine rash and may actually increase the incidence (134) Stevens-Johnson syndrome This syndrome may be diagnosed... terfenadine, 58 Antiviral Agents astemizole, warfarin, PIs, certain benzodiazepines, and certain calcium channel blockers share the same enzymatic pathway (146) Coadministration of delavirdine with these drugs and others may result in significant and potentially life-threatening adverse effects Coadministration with anticonvulsants and antimycobacterial agents Certain anticonvulsants and antimycobacterial agents. .. structure, brand names, and approved usage of didanosine areshown in Fig 2. 4 In 1993, a partially randomized study compared zidovudine alone versus Fig 2. 4 Trade names, structure, and uses of Didanosine Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 43 different combination regimens of zidovudine and didanosine The results showed more sustained increases in CD4-positive cell counts and. .. resistance, particularly in HIV-1/HBV–coinfected patients (97–99) Abacavir [ABC] (Ziagen®) Abacavir (ABC) is a second-generation NRTI given accelerated FDA approval for use in multi-drug cocktails It is a synthetic carboxycyclic nucleoside with a 6-cyclopropylamino modification The structure, brand names, and approved usage are shown in Fig 2. 8 Abacavir is the most powerful nucleoside analogue and one of... patients and can be associated with a life-threatening hepatic reaction Others report that a transient, self-limited rash develops in almost half of patients on nevirapine ( 124 ,130), typically within one to eight weeks of initiation of therapy This eruption is usually erythematous and maculopapular and can be mild or moderately severe It is typically located on the trunk, face, and extremities, and may... antiretroviral agents (Fig 2. 9) It was tested in combination with didanosine and efavirenz against a stavudine, didanosine, and efavirenz combination After 24 and 48 weeks, patients receiving the emtricitabine had significantly higher rates of virologic suppression and elevated CD4 levels than the combination recipients The dosage recommendation at this printing is one daily dose of 20 0 mg Adverse Events... capsule or in an oral solution For adults and preadults weighing at least 1 32 pounds or more, 40 mg should be taken every 12 hours For adults and Fig 2. 5 Trade names, structure, and uses of Stavudine Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections 45 preadults weighing at least 66 but not more than 1 32 pounds, 30 mg should be taken every 12 hours For children less than 66 pounds, . only when an NNRTI- or PI-based regimen cannot be used as first-line therapy. The panel’s preferred triple-NRTI regimen calls for a combination of abacavir, lamivudine, and either zidovudine. structure, brand names, and approved usage of didanosine areshown in Fig. 2. 4. In 1993, a partially randomized study compared zidovudine alone versus Fig. 2. 4 Trade names, structure, and uses of. environment. The quinolone antibiotics (e.g., ciprofloxacin) and certain antifungals, such as ketoconazole and 44 Antiviral Agents itraconazole, require an acidic environment for ab- sorption, and

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